Due to their similarities, colon and rectum cancers are generally grouped under the term of colorectal cancer (CRC). Colorectal cancer tumors grow at the expense of the mucosa of the colon (or colonic), most often in the sigmoid, which is located in the last part of the colon, with regard to colon cancers, and below this area, with regard to rectum cancers. The most common form of these cancers is called adenocarcinoma.
The normal colonic mucosa is composed of a glandular epithelium monostratified, polarized, continuous, organized in the form of crypts, limited by a basement membrane, and surrounded by lamina propria. Crypts are disposed perpendicularly to the muscularis mucosa. Lamina propria, also called chorion, has cellular (inflammatory and mesenchymal cells), stromal and vascular contents, variable according to the location in the colon. Its limitation in depth is composed by the muscularis mucosa. In lamina propria, the vascularization is limited to endothelial venules and capillaries, and to lymphatic channels superficially to the muscularis mucosa.
There are different types of benign tumors, that is to say non-cancerous colorectal tumors. The macroscopic term of polyp refers to any sessile or pedunculated mass protruding in the colonic lumen, whatever its histological nature. Histologically, adenomas are likely to turn into cancer. Hyperplastic polyps are not precancerous lesions. The same applies for inflammatory pseudo-polyps or juvenile polyps. Colonic carcinogenesis is relatively well known. In the West, colorectal cancer grows in 60-85% of cases from adenoma. This can be pedunculated, sessile or even barely in relief in the case of flat adenoma. Adenoma is a circumscribed focus of epithelial dysplasia. It is generally admitted that on 1000 adenomas, 100 will reach the size of 1 cm and 25 will evolve into cancer within 10 to 20 years. The cumulative probability of cancerous transformation of adenoma with diameter greater than or equal to 1 cm was calculated. It is of 2.5% at 5 years, 8% at 10 years and 24% at 20 years. The risk of carcinomatous transformation increases with the number, the size of adenoma (>=1 cm), the presence of villous contingent and the existence of a severe dysplasia. Adenomas presenting at least one of these criteria constitute adenomas with high risk for colonic transformation.
The adenoma-carcinoma sequence is now well established:                The prevalence of adenomas with high-risk of malignant transformation and invasive colorectal carcinomas is high in the same populations;        The peak of incidence of adenomatous polyps precedes by a few years that of cancer;        The risk of cancer depends on the number of adenomas, which explains the inevitable characters of transformation of familial polyposis that are characterized by the presence of more than 200 adenomas;        On parts of colectomy, adenoma lesions are frequently observed to the contact with infiltrating carcinomatous focus;        The incidence of colorectal cancer is decreased after exeresis of adenomas.        
The degree of dysplasia adenomas is assessed according to the differentiation, cytology and architecture abnormalities. All adenomas are dysplastic, but low-grade (formerly mild or moderate) and high-grade (severe) dysplasia are distinguished. Any benign adenoma is by definition in a low grade dysplasia, but may subsequently evolve into high-grade dysplasia adenoma, generally associated with its increase in size greater than 1 cm diameter.
In practice, adenoma-cancer sequence progresses from low grade dysplasia adenoma to invasive carcinoma, with the different steps below:                Low-grade dysplasia        High-grade Dysplasia        Tumor in situ (Tis, or intra epithelial or intra mucosal carcinoma)        Invasive carcinoma from the invasion of the submucosa.        
In a general manner, cancer in situ is a cancer in its initial stage of development, remaining limited to the tissue that gave it birth. Its definition is microscopic. In invasive carcinomas of colon, malignant cells crossed the muscularis mucosa and reached at least the submucosa (stage T1 of the TNM classification) or the muscularis mucosa (stage T2). The muscularis mucosa is a thin layer of smooth muscles, crossed by lymphoglandular complexes, vascular channels and nerve cells.
As we progress from stage T0 to stage T4, there is at tissue level a more and more significant architectural disorganization. The extension is made toward the serosa, often with a lymphatic invasion. The infiltration of cancer may be associated with vascular invasion or perinervous sheathing by tumor cells. Carcinoma may be more or less well differentiated, whatever its stage.
It is the basement membrane degradation then the crossing of the muscularis mucosa that will allow tumor cells migration and cancer spread. Invasive colorectal carcinomas are classified following the International Classification TNM as stage I to IV cancer.
Tumors in situ T0 (Tis, or intra-epithelial or intra-mucosal carcinoma) may be considered as corresponding to stage 0 which does not exist in the TNM classification, because they are not considered as cancer, since they are not invasive and not likely to be accompanied neither by a ganglionic invasion nor by metastases. However, they are lesions likely to evolve into invasive cancer and should therefore be detected to perform the exeresis and prevent the evolution into an invasive cancer.
In practice, the secretion of tumor markers is generally proportional to the tumor stage. Architectural disorganization, tissue invasion, and the presence of vascular emboli promote the release of tumor markers in biological fluids, as they promote the dissemination of cancer at a distance by the migration of tumor cells. When the basement membrane is not crossed, as is the case in the adenomas and in the noninvasive intraepithelial carcinomas, or when cancer is strictly intramucosal, the release of markers in the circulation is unlikely to happen, which is not the case when the tumor is invasive and especially when there are vascular or nervous emboli. Unexpectedly, the Applicant discovered that the protein Liver-Fatty Acid-Binding Protein (LFABP) constitutes a marker, remotely, of non-cancerous colorectal lesions and of tumors in situ. The detection of such lesions of which evolution into invasive carcinoma is significantly high, allows their exeresis, and thus to reduce the number of invasive colorectal cancer and the mortality due to this cancer.
This protein, LFABP (Swiss Prot No. P07148, also called L_FABP, FABP1, FABPL, protein Z or sterol transporter protein) belongs to the FABP family which comprises nine isoforms. Each isoform is named according to the tissue in which it was detected for the first time. These isoforms possess a community of functions, similar three-dimensional structures but their sequence homology is not high. The LFABP has been sequenced in 1985. It is a small protein of 15 kDa, abundant in the cytosol and having the ability to bind to free fatty acids and also to bilirubin.
For colon cancer, several groups identified a decrease in the expression of LFABP protein in the tumor tissue (neoplastic or pre-neoplastic) compared to normal colonic mucosa, by using 2 dimensions electrophoresis techniques. This result was also confirmed by immunohistochemistry techniques. Tissue expression of LFABP is decreased in primary colorectal tumor in patients with ganglionic nodes compared to patients without ganglionic nodes.
Furthermore, the expression of mRNA of LFABP and the protein itself are decreased during the sequence “normal tissue/adenoma/colorectal cancer”, as it has been demonstrated by many authors [Lee et al., Differential expression in normal-adenoma-carcinoma sequence suggests complex molecular carcinogenesis in colon. Oncol Rep. 2006 October; 16(4):747-54], which means that LFABP should be fewer in adenomas tissue than in normal tissue. Lauriola et al. [Lauriola M et al., Identification by a Digital Gene Expression Displayer (DGED) and test by RT-PCR analysis of new mRNA candidate markers for colorectal cancer in peripheral blood. Int J Oncol. 2010 August; 37(2):519-25] tried to quantify mRNA circulating in blood for the LFABP and other markers, without managing to detect LFABP neither in cancer patients nor in control subjects.
In patent application WO2009/019368A2, the Applicant highlighted the fact that the detection of LFABP protein, in combination with CEA markers (carcinoembryonic antigen) and CA 19-9, allowed improving the detection of colorectal cancer patients.